Transforming growth factor‐β signaling confers hepatic stellate cells progenitor features after partial hepatectomy

Liver regeneration involves not only hepatocyte replication but progenitor aggregation and scarring. Partial hepatectomy (PH), an established model for liver regeneration, reactivates transforming growth factor-beta (TGF-beta) signaling. Hepatic stellate cells (HSCs) are primarily responding cells for TGF-beta and resident in stem cell niche. In the current study, PH mice were treated with SB-431542, an inhibitor of TGF-beta Type I receptor, aiming to address the role of TGF-beta signaling on the fate determination of HSCs during liver regeneration. After PH, control mice exhibited HSCs activation, progenitor cells accumulation, and a fraction of HSCs acquired the phenotype of hepatocyte or cholangiocyte. Blocking TGF-beta signaling delayed proliferation, impaired progenitor response, and scarring repair. In SB-431542 group, merely no HSCs were found coexpressed progenitor makers, such as SOX9 and AFP. Inhibition of TGF-beta pathway disturbed the epithelial-mesenchymal transitions and diminished the nuclear accumulation of beta-catenin as well as the expression of cytochrome P450 2E1 in HSC during liver regeneration. We identify a key role of TGF-beta signaling on promoting HSC transition, which subsequently becomes progenitor for generating liver epithelial cells after PH. This process might interact with an acknowledged stem cell function signaling, Wnt/beta-catenin.